LCMV is the prototypic member of the Arenaviridae family, a family of enveloped RNA viruses (2). Arenavirus infection in rodents, the natural host animal, is usually chronic and asymptomatic. Several arenaviruses can cause severe hemorrhagic fever in humans, including Lassa, Machupo, Guanarito, and Junín viruses. Transmission to humans can result from direct contact with infected rodents or their habitat, through aerosolized rodent secretions, or through contact with the body fluids of an infected person. LCMV is found world-wide, reflecting the range of the Mus musculus rodent host. The Arenaviridae family contains a single genus (Arenavirus) that is divided into two major lineages based on phylogenetic and serological examination. LCMV is a member of the Old World arenaviruses, which includes the Lassa fever virus, a Category A hemorrhagic fever virus.
In 1999, the Centers for Disease Control and Prevention (CDC) identified and categorized potential biological terrorism agents as part of a Congressional initiative to upgrade bioterrorism response capabilities (12). Arenaviruses were designated as Category A, defined as those pathogens with the highest potential impact on public health and safety, potential for large-scale dissemination, capability for civil disruption, and greatest unmet need for public health preparedness. The National Institute of Allergy and Infectious Diseases (NIAID) has continued to update the Category A list (6), specifically listing LCMV as a Category A virus (7).
Although LCMV is closely related to other arenaviruses known to cause hemorrhagic fever, LCMV has been linked to only a very limited number of cases in which patients exhibited hemorrhagic fever-like symptoms (11). More often, exposure to the virus results in a characteristic biphasic pattern of illness, beginning with flu-like symptoms characterized by fever, headache, myalgia, malaise, and fatigue after an incubation period of 1-3 weeks. Following a few days of recovery, a second phase of disease can occur in which patients exhibit symptoms of meningitis (fever, headache, or stiff neck) or encephalitis (drowsiness, confusion, sensory disturbances, and/or motor abnormalities). Studies conducted between 1941 and 1958 at Walter Reed Medical Center show that about 10% of febrile diseases with central nervous system involvement were due to LCMV (1, 5). While meningitis and encephalitis patients require hospitalization and supportive care based on severity of symptoms, infected individuals usually recover fully without sequelae, although nerve deafness and arthritis have been reported. Mortality resulting from LCMV infection is rare, occurring in less than 1% of cases (11).
LCMV can be transmitted from an infected pregnant woman to the developing fetus resulting in severe teratogenic consequences including hydrocephaly, microcephaly or macrocephaly, and chorioretinitis (14). These conditions commonly lead to severe developmental delays, mental retardation, blindness, and premature death. The incidence of congenital LCMV infection among infants born in the US has not been established (14).
Recently, new manifestations of LCMV-associated diseases have been reported in the medical literature (3). In 2002 and again in 2005, LCMV was transmitted to patients receiving immunosuppressive medications after they received transplanted organs from an infected donor. Out of eight organ recipients, seven died from the infection. The donors exhibited no clinical signs of LCMV infection and subsequent diagnostic investigations failed to detect the virus. Nevertheless, the coincidence in timing and phylogenetic matching of strains within each cluster provide convincing evidence regarding the origins of the infecting agents (3).
Prevention and treatment options for LCMV are limited. No licensed vaccines or FDA-approved antiviral drugs are available. Although ribavirin has shown limited antiviral activity against LCMV in vitro, there exists no established data supporting its routine use in humans. Thus there remains a need to develop safe and effective products to protect against LCMV infections.
The arenavirus genome consists of two segments of single-stranded RNA, each of which codes for two genes in opposite orientations (referred to as ambisense). The larger of the two segments, the L RNA (7.2 kb), encodes the L and Z proteins. The L protein is the RNA-dependent RNA polymerase (RdRp), and the Z protein is a small zinc-binding RING finger protein which is involved in virus budding (10). The S RNA (3.4 kb) encodes the nucleoprotein (NP) and the envelope glycoprotein precursor (GP-C). The nucleocapsid consists of genomic RNA tightly encapsidated by viral NP, the most abundant viral protein in virions and infected cells.
The L protein is a circa 254 kDa multifunctional enzyme that possesses characteristics shared with over 80 RdRps from negative-strand viruses, including six conserved domains that appear to correspond to essential functional features required to synthesize RNA from RNA template (13). Viral RNA, NP, and L combine to form a ribonucleoprotein complex, which transcribes and replicates the viral genome (4). Because mammalian cells lack homologs of the L and NP proteins, the potential to specifically inhibit these enzymes without compromising essential host processes make NP and L attractive targets for antiviral therapeutic development efforts.